System and method for delivery of biologic agents

ABSTRACT

A delivery system for delivering a therapeutic agent to a patient includes a catheter, a stop feature, a container and a bar. The catheter has a proximal end and a distal end and includes a body defining a lumen that extends to the distal end of the catheter. The stop feature is in proximity to the distal end of the catheter. The container is configured to house the therapeutic agent and is insertable and slidably disposable in the lumen of the catheter. The container is also configured to engage the stop feature of the catheter. The bar is slidably disposable in the lumen of the catheter. Sliding of the bar distally in the lumen forces the therapeutic agent out of the container and out of the lumen when the container is engaged with the stop feature. The stop feature is configured to inhibit the container from exiting the lumen.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.12/262,798, filed Oct. 31, 2008.

FIELD

This disclosure relates to medical devices, systems and methods fordelivering biologic agents to a patient.

BACKGROUND

Systems for delivering biologic agents in an operating room settingcurrently include the biologic agent and a delivery device. Amapping/navigation system, and a monitor for viewing the deliveryprocess may also be used. The biologic agent is typically delivered tothe operating room in an appropriate volume and concentration in aclosed container, such as an Eppendorf tube. Once in the operating roomand when the delivery device is ready to receive this biologic agent,the biologic agent is transferred from the container to a syringe whichis in turn connected to the delivery device. The biologic agent is thencarefully delivered from the syringe through the delivery device intotarget tissue.

The steps involved in such a process present several areas forimprovement. For example, the transfer of the biologic agent from thecontainer to the delivery system involves exposing the agent to theenvironment, risking contamination. Also, the transfer provides thepotential for spilling and loss of the biologic agent, as well aspotentially inaccurate amounts being delivered. Further, the number ofdifferent materials that the biologic agent contacts may be quite high.For example, the biologic agent contacts the container, such as theEppendorf tube, the syringe, and the delivery device, allowing forpossible compatibility issues and losses due to adhesion and adsorptionto the container, syringe and delivery device.

Another source of potential concern with current methods for deliveringbiologic agents is excessive shear stress being placed on the biologicagent as it is delivered through the delivery system. The deliverysystem typically includes catheters having very small inner diameters;e.g., 29-27G or about 0.007 inches to 0.009 inches. The inner diametersof the catheters are purposefully kept small to reduce dead space andthus to minimize the amount of deliverable biologic agent lost duringthe procedure. Exposure to shear stress may greatly reduce the efficacyof the biologic agent delivered, particularly cells.

BRIEF SUMMARY

This disclosure describes, inter alia, a system for delivering biologicagents that allows for delivery of biologic agents in a container via acatheter to a target tissue of a patient. As disclosed herein, anappropriate or predetermined amount of biologic agent may be transferredinto the container in a sterile environment. In the operating room, thecontainer is placed in a catheter having a distal end implanted at atarget tissue site of a patient and is moved to the distal end of thecatheter, where its contents are released into the target tissue.

In an embodiment, a delivery system for delivering a therapeutic agentto a patient is described. The delivery system includes a catheter, astop feature, a container and a bar. The catheter has a proximal end anda distal end and includes a body defining a lumen that extends to thedistal end of the catheter. The stop feature is in proximity to thedistal end of the catheter. The container is configured to house thetherapeutic agent and is insertable and slidably disposable in the lumenof the catheter. The container is also configured to engage the stopfeature of the catheter. The bar is slidably disposable in the lumen ofthe catheter. Sliding of the bar distally in the lumen forces thetherapeutic agent out of the container and out of the lumen when thecontainer is engaged with the stop feature. The stop feature isconfigured to inhibit the container from exiting the lumen.

In an embodiment, a method for delivering a therapeutic agent to atarget tissue of a patient is described. The method includes (i) placinga distal end of a catheter having a lumen in the target tissue; (ii)inserting a container housing the therapeutic agent in the lumenproximal to the distal end of the catheter; (iii) moving the containerin the lumen distally; and (iv) releasing the therapeutic agent from thecontainer in proximity to the distal end of the catheter.

In an embodiment, a container for housing a therapeutic agent isdescribed. The container includes a body member, a sealing element, anda rupturable membrane. The body member has a proximal end and a distalend and a lumen that extends from the proximal end to the distal end.The sealing element is slidably disposable in the lumen. The sealingelement is configured to sealingly engage the body member as the elementis slid within the lumen. The rupturable membrane is disposed across thelumen in proximity to the distal end of the body member.

In an embodiment, a delivery system for delivering a therapeutic agentto a patient is described. The delivery system includes a catheter and acontainer for housing the therapeutic agent. The catheter has a proximalend and a distal end. The catheter has a body that defines a lumenextends from the proximal end to the distal end. The catheter furtherincludes a stop feature in proximity to the distal end. The container isinsertable and slidably disposable in the lumen of the catheter. Thecontainer is configured to engage the stop feature of the catheter. Thesystem further includes means for forcing therapeutic agent out o thecontainer and out of the lumen when the container engages the stopfeature.

One or more of the various embodiments presented herein provide one ormore advantages over prior proposed methods, devices or systems fordelivering biologic agents to a target tissue of a patient. For example,placing a container housing the biologic agent directly into thedelivery system reduces exposure of the biologic agent to theenvironment and thus reduces the potential for contamination. This alsoreduces compatibility issues as the number of different materials thatthe biologic agent is exposed to is reduced, as the biologic agent ispresent in the container until it is delivered to the patient. Further,the amount of shear stress to which the biologic agent is subject may begreatly reduced, due e.g. to the biologic agent being static withrespect to the container for the length of the catheter. These and otheradvantages will be readily understood from the following detaileddescription when read in conjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a partially implanted catheter in theenvironment of a patient.

FIG. 2 is a schematic exploded perspective view of a representativedelivery system.

FIG. 3 is a schematic side view of an assembly that includes a catheterand tube with complementary connector fittings.

FIGS. 4A-D are schematic longitudinal cross sections of representativecatheters.

FIGS. 5A-B and 6A-B are schematic longitudinal cross sections ofrepresentative containers.

FIGS. 7A-D, 8A-C, 9A-B, 10A-C, and 11 are schematic longitudinal crosssections of representative delivery systems.

FIG. 12-14 are block diagrams of representative components of controland drive systems of representative delivery systems

FIG. 15 is a schematic longitudinal cross section of a representativecontainer.

FIGS. 16 and 17A are schematic side views of representative two-partcontainers.

FIG. 17B is a schematic longitudinal cross section of the containerdepicted in FIG. 17A.

FIGS. 18-19 are schematic longitudinal cross sections of representativecontainers.

FIG. 20 is a block diagram of a container having two chambers.

FIGS. 21-22 are schematic longitudinal cross sections of representativemulti-part containers capable of forming two chambers.

The drawings are not necessarily to scale. Like numbers used in thefigures refer to like components, steps and the like. However, it willbe understood that the use of a number to refer to a component in agiven figure is not intended to limit the component in another figurelabeled with the same number. In addition, the use of different numbersto refer to components is not intended to indicate that the differentnumbered components cannot be the same or similar.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings that form a part hereof, and in which are shown byway of illustration several specific embodiments of devices, systems andmethods. It is to be understood that other embodiments are contemplatedand may be made without departing from the scope or spirit of thepresent disclosure. The following detailed description, therefore, isnot to be taken in a limiting sense.

All scientific and technical terms used herein have meanings commonlyused in the art unless otherwise specified. The definitions providedherein are to facilitate understanding of certain terms used frequentlyherein and are not meant to limit the scope of the present disclosure.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” encompass embodiments having pluralreferents, unless the content clearly dictates otherwise. As used inthis specification and the appended claims, the term “or” is generallyemployed in its sense including “and/or” unless the content clearlydictates otherwise.

As used herein, “have”, “having”, “include”, “including”, “comprise”,“comprising” or the like are used in their open ended sense, andgenerally mean “including, but not limited to”.

As used herein, the terms “treat”, “therapy”, and the like meanalleviating, slowing the progression, preventing, attenuating, or curingthe treated disease.

As used herein, “disease”, “disorder”, “condition” and the like, as theyrelate to a subject's health, are used interchangeably and have meaningsascribed to each and all of such terms.

The present disclosure describes, inter alia, systems, devices andmethods for delivering biologic agents to a target tissue of a patient.A container housing a therapeutic agent may be placed directly into adelivery system and delivered to the target tissue site where thetherapeutic agent may be released. The therapeutic agent may be abiologic agent, such as a cell, a virus, a polypeptide, a polynucleotideor the like. Many of such biologic agents are susceptible tocomplications due to shear stress due to their large size or molecularweight. The therapeutic agent may be formulated in a solution,suspension, dispersion, or the like or may be in solid form.

Referring now to FIG. 1, a catheter 100 of a representative deliverysystem is schematically shown in the environment of a patient. Thecatheter 100 has a proximal end 110 and a distal end 120. In thedepicted embodiment, the proximal end 110 of the catheter 100 exteriorto the patient, and the distal end 120 is implanted in the patient at atarget tissue location, in this case in the pericardial sac 6 of theheart 8. Biologic agents that are administered intravenously have arelatively short time for contacting cardiac tissue compared to agentsdelivered into the pericardium. Of course, in various embodiments, itmay be desirable to deliver the agent intramyocardially, intracoronaryor into the heart in any other suitable manner. While the catheter 100in FIG. 1 is depicted as being implanted for delivery of an agent to theheart 8, it is contemplated that the delivery systems and methodsdescribed herein may be used to deliver agent to any suitable targettissue of a patient, including any suitable subcutaneous tissue,including brain parenchyma, spinal canal, perispinal tissue,cerebrospinal fluid, spleen, pancreas, stomach, intestine, kidney,liver, muscle, and the like.

Referring now to FIGS. 2-3, a schematic illustration of somerepresentative components of a delivery system 1000 is shown. Thedepicted delivery system 1000 includes a catheter 100, a capsule orcontainer 200 for housing a biologic agent, and a bar 300. The catheter100 has a proximal end 110 and a distal end 120 and a body memberdefining a lumen that extends from the proximal end 110 to the distalend 120 of the catheter 100. The container 200 is configured to house abiologic agent and is insertable into the lumen of the catheter 100 andslidably disposable in the lumen. The bar 300 is also slidablydisposable in the lumen of the catheter 100, as will be described inmore detail below. In the embodiment depicted in FIG. 2, a pushingmember 350 is coupled to the distal end 320 of the bar 300. The pushingmember 350 may be integrally formed with, connected, attached, bonded,or otherwise coupled to the bar 300.

As shown in FIG. 2, an opening 130 is formed in the body of the catheter100. The opening 130 forms a bore in the catheter 100. The boreintersects the lumen of the catheter 100 and is substantiallyperpendicular to the axis of the lumen. The opening 130 is configured toreceive the container 200 such that the container 200 may be placed inthe opening 130 to gain access to the catheter lumen. A cover (notshown) or other member may sealingly engage the opening 130. The coveror other member may be removed or opened to insert the container 200into the opening 130, and replaced to sealingly engage the opening 130after the container 200 is inserted in the opening. It will beunderstood, that when catheter 100 does not include such an opening 130for receiving the container 200, the container 200 may be inserted intothe catheter lumen via an opening at the proximal end 110 of thecatheter, through which the lumen extends.

As shown in FIG. 3, the proximal end 110 of the catheter 100 may includea connection fitting 140 for sealingly coupling to tube 500 having acomplementary connection fitting 510. The embodiment depicted in FIG. 3may be desirable when hydraulics are use to control movement of the barwithin the lumen of the catheter 100.

Referring now to FIG. 4A, a schematic illustration of a cut away view ofthe catheter 100 shown in FIG. 2 (along line 4-4) with bar 300 andcontainer 200 disposed within the lumen 150 is shown. Again, catheter100 has a proximal end 110 and a distal end 120 and a body member 140defining a lumen 150 extending from the proximal end 100 to the distalend 120. The container 200 and bar 300 are slidably disposable in thelumen 150. In the depicted embodiment, a pushing member 350 is coupledto the bar 300. The bar 300 and pushing member 350 are positioned in thelumen 150 of the catheter 200 such that the pushing member 350 iscapable of engaging the container 200 and pushing the container 200distally in the lumen 150 when the bar 300 is slid distally in the lumen150.

Referring now to FIGS. 4B-D, longitudinal cross sections ofrepresentative embodiments of catheters 100 are shown. For purposes ofillustration, the sections can be considered as being taken along line4-4 of the catheter 100 depicted in FIG. 2. The catheters 100 depictedin FIGS. 4B-D have a proximal end 110, a distal end 120, and a bodymember 140 defining a lumen 150 extending from the proximal end 110 tothe distal end 120. A stop feature 400 is positioned in proximity to(e.g., at or near) the distal end 120 of the catheter 100. The stopfeature 400 extends into the catheter lumen 150 and is configured toengage the container 200 to inhibit or prevent the container fromexiting the lumen 150 at the distal end 120 of the catheter 100. It willbe understood, as described below with regard to various embodiments,the stop feature 400 is intended to inhibit or prevent the entirety ofthe container 200 from exiting the lumen 150, as a portion of thecontainer 200 may exit the lumen 150. The stop feature 400 may beintegrally formed with, bonded to, adhered to, affixed to, or otherwisecoupled to the body 140 of the catheter 100. As shown in FIG. 4D, a stopfeature 400 may include a piercing element 410 positioned and configuredto pierce the container, as described in more detail below with regardto various embodiments.

As shown in FIG. 4C, a filter 600 or screen may be disposed across thecatheter lumen 150 in proximity to the distal end 120. The filter 600 orscreen may prevent unintended particulate matter from exiting the lumen150 into target tissue of a patient when the catheter is put to use. Inthe embodiment depicted in FIG. 4B, the stop feature 400 may serve as afilter or screen in addition to serving to inhibit or prevent thecontainer from exiting the lumen.

A catheter as described herein may be made of any suitable material orcombinations of material. For example, the body of the catheter may beformed from a suitable polymeric material, such as PTFE, ETFE,polyethylene, polypropylene, polycarbonate, or combinations of polymericmaterials and may include reinforcing elements such as braids or meshes.In various embodiments, the catheter may be formed from silicone orpolyurethane.

A catheter as described herein may have any suitable dimensions tocarryout its intended therapeutic purpose. For example, the catheter ispreferably long enough to allow its distal end to be implanted in atarget tissue location and to allow its proximal end to be external tothe patient. The diameter of the catheter lumen is sized to allowmovement of a bar, pushing member if employed, and container within thelumen.

A bar as described herein may be made of any suitable material orcombinations of material. When the catheter is flexible and follows anon-linear path through the body of a patient to the target tissue, thebar is preferably sufficiently flexible to follow the non-linear pathwithin the catheter. However, for many therapies, the path that thecatheter follows in the patient's body should be substantially linear.In such situations, the bar may be less flexible. In variousembodiments, the bar is formed from silicone rubber, butyl rubber,fluorocarbon rubber, neoprene, polyurethane, polyethylene,polypropylene, polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA),fluorinated ethylene propylene (FEP), ethylene-propylene copolymers,polystyrene, polycarbonate, metals such as stainless steel or nitinol,glass or the like.

A pushing element as described herein may be made of any suitablematerial or combinations of material. For example, a pushing element maybe formed from materials similar to those enumerated above with regardto the bar.

A piercing element as described herein may be made of any suitablematerial or combinations of material. In various embodiments, thepiercing element is formed from a rigid polymeric material, such aspolystyrene, high density polyethylene, polycarbonate, or the like.

A filter as described herein may be made of any suitable material orcombinations of material. For example, a pushing element may be formedfrom materials similar to those enumerated above with regard to pushingmember.

Referring now to FIGS. 5-6, schematic illustrations of cross sections ofrepresentative containers 200 are shown. In the embodiment depicted inFIG. 5A, the container 200 includes a housing 210 defining a reservoir220 for containing a biologic agent. In various embodiments, the wall isformed from an elastomeric material and the volume of the reservoir 220is variable. In numerous embodiments, the housing 210 is sufficientlystiff to maintain its shape to ensure proper slidability within a lumenof a catheter of a delivery system. Regardless of the degree ofstiffness of housing 210, the container 200 is configured such thatforce applied to one face (e.g., in the direction of line F), or aportion thereof, of the container 200, while the opposing face issubstantially stationary, causes the face on which force is exerted tomove towards the opposing stationary face to force contents out of thereservoir. In various embodiments, the housing 210 is configured to bepiercable by a piercable element, to allow contents of the reservoir 220to escape, and in some embodiments, to reduce internal reservoirpressure so that such pressure does not overcome force F.

In the embodiment depicted in FIG. 5B, a rupturable membrane 250sealingly engages the interior perimeter of a wall 212 of the housing210 such that the rupturable membrane 250 and the housing togetherdefine the reservoir 220 for containing a biologic agent. While notshown, it will be understood that rupturable membrane 250 may sealinglyengage an exterior perimeter of the wall 212. The membrane 250 may bebonded, adhered, affixed or otherwise attached or sealingly engaged tothe wall 212. The rupturable membrane 250 may be piercable by apiercable element of a catheter of a delivery system, may rupture uponincreased pressure (e.g., when force F is applied), may include a lineof weakening along which the rupture may occur, or the like. In variousembodiments, the rupturable membrane 250 is a self sealing septum thatallows introduction of the biologic agent into the reservoir 220 via aneedle (not shown) and sealingly contains the biologic agent uponwithdrawal of the needle.

Referring now to FIGS. 6A-B, container 200 includes a body member 210having a proximal end 202 and a distal end 204. The body member 210defines a lumen extending from the proximal end 202 to the distal end204. The container further includes a sealing element 230 slidablydisposable within the lumen of the container 200. The sealing element230 is configured to sealingly engage the body member 210 as the element230 is slid within the lumen. In the depicted embodiment, the sealingelement 230 includes an O-ring 235 for sealingly engaging the bodymember 210 within the lumen. Of course, sealing element 230 may form aseal in any suitable manner. For example, sealing member may includewiper seals or the like. A rupturable membrane 250 is disposed acrossthe lumen in proximity to the distal end 204 of the body member 200. Areservoir 220 for containing a biologic agent is formed between therupturable membrane 250, the sealing element 230 and the body member210.

The housing of the container may be made of any suitable material. Forexample, the housing, or portions thereof, may be formed from, glass,silicanized stainless steel, silicanized titanium, nitinol, polystyrene,polyethylene, polycarbonate, ethylene vinyl acetate, polypropylene,polysulfone, polymethylpentene, polytetrafluoroethylene (PTFE) orcompatible fluoropolymer, a silicone rubber or copolymer,poly(styrene-butadiene-styrene), polyurethane or the like, or acombination thereof. In various embodiments, the housing is made ofpolyurethane. It will be appreciated that the material of choice andthickness of the housing may be varied depending on the whether anelastic or rigid housing is desired.

Body (as shown in FIGS. 6A-B) may be formed of any suitable material.For example, body member may be formed of the same or similar materialsas those described above with regard to a rigid housing.

Surfaces of the housing or other portions of a container that may comeinto contact with the biologic agent may be treated or coated to improvecompatibility with the biologic, reduce adherence of the biologic agent,or the like.

Rupturable membrane may be made of any suitable material, such as thoseenumerated above with regard to housing. In some embodiments, whererupturable membrane is a sealable septum, the membrane is made from asuitable elastomeric material, such as silicone rubber, butyl rubber,fluorocarbon rubber, polyethylene, polypropylene,polytetrafluoroethylene (PTFE) or the like. In many embodiments, themembrane is permeable to atmospheric gasses but is impermeable toaqueous liquids. In such embodiments, the membrane may be formed frompolystyrene, polycarbonate, ethylene vinyl acetate, polysulfone,polymethylpentene, polytetrafluoroethylene (PTFE) or compatiblefluoropolymer, a silicone rubber or copolymer,poly(styrene-butadiene-styrene), or polyolefin, such as polyethylene orpolypropylene, or combinations of these materials. It will be understoodthat desired thickness may vary depending on the material from which themembrane is formed. By way of example, the membrane may be between about0.02 millimeters and 0.8 millimeters thick.

Sealing member (moveable wall) may be formed from any suitable material.If the sealing member is a one-piece element formed from a singlematerial, sealing member may be formed from a suitable elastomericmaterial, such as silicone rubber, butyl rubber, fluorocarbon rubber,neoprene, polyurethane, polyethylene, polypropylene,polytetrafluoroethylene (PTFE), perfluoroalkoxy (PFA), fluorinatedethylene propylene (FEP), ethylene-propylene copolymers, or the like Ifsealing element includes a separate sealing feature, such as an O-ring,wiper seal, or the like, the non sealing feature of the sealing elementmay be formed, for example, materials as enumerated above with regard tohousing.

In various embodiments, the housing, sealing member, and rupturablemembrane are all made of the same material to reduce the number ofmaterials that the therapeutic agent contacts. For example, the housing,sealing member, and rupturable membrane may all be formed frompolyurethane.

Referring now to FIGS. 7-11, longitudinal cross sections of somecomponents of representative delivery systems 1000 are shown. In thevarious embodiments depicted in FIGS. 7-11, a container 200 is slidablydisposed in a lumen 150 of a catheter 100. A bar 300 including adistally located pushing element 350 is slidably disposed in the lumen150. The container 200 is positioned in the lumen 150 distally relativeto the bar 300 and pushing element 350. As the bar 300, 500 is sliddistally in the lumen 150, the pushing element 350, 550 engages thecontainer 200 and causes the container 200 to slide distally in thelumen 150. Stopping feature(s) 400 located in proximity to (i.e.,generally at or near) the distal end 120 of body member 140 inhibit orprevent container 200, or a portion thereof, from exiting the lumen 150of the catheter 100. When the stop feature(s) 400 engage the container200, further distal movement of bar 300, 500 in lumen forces thecontents (not shown) of the container 200 out of the container 200 andout of the distal end of the lumen 150.

In the embodiment depicted in FIGS. 7A-D, piercing element 410 pierces aportion of the face of the container housing 210′ facing the distal end120 of the catheter body 140 as the container moves distally in thecatheter lumen 150. Further distal movement of bar 300 in lumen 150forces contents (not shown) out of the container 200 and out of thedistal end of the lumen 150 through the pierced region. In addition, theside walls 210″, 210″′ of the container housing collapse as the bar ismoved distally when the container 200 engages the stop feature 400 (seeFIG. 7D). The side walls 210″, 210″′ may be in the form of a bellows,may be sufficiently deformable to collapse, or the like. In variousembodiments (not shown), the piercing element 410 may be a needleadvanced distally through the lumen 150 of the catheter 100 and throughthe container 200. For example, the needle (not shown) may be insertedthrough a lumen (not shown) of the bar 300. The needle may have anetched surface for piercing the container 200 or may have a surface thatis covered with an array of microneedles to allow for more spreadoutdistribution of the agent.

As further shown in FIG. 7D, a screen 600 or filter may be disposed inthe catheter lumen 150 in proximity to the distal end 120 to inhibit orprevent unintended particulate matter, such as parts of the containerhousing 210, from exiting the lumen 150. As further shown in theembodiment depicted in FIGS. 7A-D, pushing element 350 includes asealing element 355, such as an O-ring, so that pushing element 355sealingly engages body 140 in lumen 150. By sealingly engaging body 140in lumen 150, pushing element 350 can inhibit or prevent contents thatleave container 200 from moving proximally in the lumen 150. In variousembodiments, pushing element 350 does not sealingly engage body 140 ofcatheter 100.

Referring now to FIGS. 8A-C, a container 200 similar to that depicted inand discussed with regard to FIGS. 6A-B is shown disposed in catheterlumen 200 distally to bar 300. The bar 300 is slidably disposed in lumen510 a second bar 500, which is slidably disposed in the lumen 150 of thecatheter 100. The second bar 500 includes a body member 520 that definesthe lumen 510. The second bar 500 includes a pushing member 550 at thedistal end of the bar 500. The second pushing member 550 includes anopening 530 axially aligned with the lumen 512. The first bar 300 isaxially slidable in the lumen 510 of the second bar 500 and extendablebeyond the opening 530. The second pushing member 550 is configured toengage the container 200 and move the container 200 distally in thecatheter lumen 150 as the second bar 500 slides distally in the catheterlumen 150. The second bar 500 pushes the container 200 distally in thecatheter lumen 150 until the container 200 engages stop feature 400. Ifthe second bar 500 is moved manually within the catheter lumen 150,tactile feedback that the container 200 has engaged the stop feature 400may indicate to the user that no further distal pushing of the bar 500is desirable. If the bar 500 is moved via an automated mechanism,feedback, such as increased resistance to movement, increased pressureon stop feature, increased power consumption without further movement orthe like may be used to indicate that further distal movement of the bar500 should be ceased.

In the embodiment depicted in FIGS. 8A-C, distal movement of the secondbar 500 causes distal movement of the first bar 300, as the secondpushing element 550 engages the first pushing element 350 and pushes thefirst pushing element 350 distally as the second bar 500 is sliddistally in catheter lumen 150. At a point where the second bar 500 ispushed distally such that the container 200 engages stop feature 400,the first bar 300 may be moved distally to force contents (not shown)out of the container 200 and out of the catheter 100. In the embodimentshown, the pushing element 350 of the first bar 300 is configured toengage the moveable sealing member 230 of the container 200. As thefirst bar 300 is moved distally when the container 200 is engaged withstop feature 400, the pushing element 350 moves the sealing member 230distally forcing contents out of container 200 via rupturable membrane250. While not shown, it will be understood that a filter or screen maybe disposed across the catheter lumen 150 (e.g., as shown in FIG. 7-D).

Referring now to FIGS. 9A-B, an embodiment similar to that shown inFIGS. 8A-C is shown, with like numbers referring to like parts. In theembodiment shown in FIGS. 9A-B, the stop feature 400 includes piercingelements 410. When the container 200 is pushed distally in catheterlumen 150 such that the container 200 engages the stop feature 400,piercing element 410 pierces rupturable membrane 250. As the sealingmember 230 is moved distally, contents of the container 200 can exit viathe pierced portion of the membrane 250.

Referring now to FIGS. 10A-C, an embodiment similar to that shown inFIGS. 8A-C is shown, with like numbers referring to like parts. In FIG.10, container 200 includes a tapered distal region configured to extendbeyond the distal end 120 of the catheter 100 when the stop feature 400engages the container 200. In various embodiments, the distal taperedregion of the container 200 has a sufficiently large inner diameter toavoid subjecting the contents of the container 200 to shear stress asthe contents are forced through the distal tapered region. As shown inFIG. 10, the sealing member 230 of the container 200 may be sized andshaped in a similar manner to the distal tapered region to increase theamount of contents that may be forced out of the container 200.

Referring now to FIG. 11, a bar 300 or pushing member 350 of the bar mayserve as a sealing member of a container. In the depicted embodiment,pushing member 350 sealingly engages the body of the container as thepushing member 350 is moved distally within the container to forcecontents out of the container.

While not shown, it will be understood that mechanisms other than bars300, 500 may be used to move container 200 distally in lumen 150 andforce contents out of the container 200. For example, air pressure orhydraulic fluid pressure (e.g., saline) may be used to move thecontainer 200 and provide force to release contents. In suchembodiments, it may be desirable for the container 200 to sealinglyengage the body 140 of the catheter 100. It will be further understoodthat a bar 300, 500 may be moved in the lumen 150 by any suitablemechanism, such as hydraulic fluid pressure, air pressure, motor,manually, or the like.

Referring now to FIGS. 12-14, block diagrams of some representativecomponents of automated systems for moving bars as discussed abovewithin lumens of catheters are shown. In the simple form shown in FIG.12, such a system may include a controller 2100, a driving mechanism2200, and a bar 300. Any suitable controller 2100, such as amicroprocessor, may be employed to control the driving mechanism 2200.Any suitable driving mechanism 2200 may be employed to move bar 300. Invarious embodiments, the driving mechanism 2200 is a motor, such as astepper motor. In some embodiments, the driving mechanism 2200 is ahydraulic or air pressure driving mechanism. In such embodiments, thebar 300 preferably sealingly engages the body of the catheter to preventhydraulic fluid from leaking in the lumen distal to the bar 300. Asshown in FIGS. 13-14, in embodiments where first 300 and second 500 barsare employed, a single drive mechanism 2200 may be used to drive bothbars 300, 500 or a first drive mechanism 2210 may be used to move thefirst bar 300 and a second drive mechanism 2220 may be used to move thesecond bar 500.

Referring now to FIGS. 15-22, schematic illustrations of variousconfigurations of containers 200 useful in delivery systems as describedabove are shown. In FIG. 15, a schematic longitudinal cross section of acontainer 200 is shown. The container 200 includes a sealing element 230and a rupturable membrane 250. The rupturable membrane 250 may be a selfsealing septum to allow contents to be added to the container 200. Thesealing element 230 includes a piercing element 290 configured to piercerupturable membrane 250 to allow contents to exit the container 200 whenthe sealing member 230 is moved distally. As shown in the schematic sideview of FIG. 16, a container 200 may include first 260 and second 270connectable portions. The second portion 270 may serve as a removableand resealable cap. The cap may be removed so that contents may be addedto the first portion 260 and resealed to prevent the contents of thecontainer 200 from leaking or spilling. The first 260 and second 270portions include complementary mating features 261, 271 to allowdisconnecting and reconnecting of the first and second parts. In thedepicted embodiment, the first portion 260 includes external threads261. The second portion 270 includes complementary internal threads 271(represented by internal dashed lines). Of course, any other suitableform of connection may be employed. As shown in FIGS. 17A-B, which issimilar to the embodiment depicted in FIG. 16 with like numbersreferring to like parts, the second portion 270 of the container 200 mayinclude a rupturable membrane 250. In the embodiment depicted in FIG.18, the first part 260 includes a sealing element 230 and the secondpart 270 includes a rupturable membrane 250.

Referring now to FIG. 19, container 200 may include an outer sheath 280that surrounds the housing 210 of the container. In various embodiments,the outer sheath 280 may be removed in the operating room prior toinsertion of the container 200 into the lumen of a catheter of adelivery system. The sheath 280 may thus prevent excessive exposure (andthus contamination) of the housing 210 prior to delivery of itscontents. In some embodiments, the outer sheath 280 may be removablefollowing insertion into the catheter so that physician contact with theinner housing 210 is prevented. Of course, the outer sheath 280 andhousing 210 may be ruptured in proximity to the distal end of thecatheter as the agent disposed in the housing is released. In variousembodiments, the outer sheath 280 is permeable to atmospheric gases, butimpermeable to aqueous liquids. Such breathable outer sheaths 280 may bedesirable when the container 200 houses cells and it is desirable topreserve the viability of the cells prior to delivery.

Referring now to FIG. 20, a container 200 may be sealingly subdividedinto first 298 and second chambers 299. The first 298 and second 299chambers may house different agents that may not be compatible if storedtogether. In various embodiments, the first chamber 298 houses afluoroscopic medium to enable visualization via imaging techniques andthe second chamber 299 houses a biologic agent. Just prior tointroduction into a patient through the use of a delivery system asdescribed above, the contents of the first 298 and second 299 chambersmay be mixed. FIGS. 21-22 depict schematic longitudinal cross sectionsof two embodiments of such two-compartment containers.

In the embodiment depicted in FIG. 21, the container 200 includes first260, second 270, third 260′ and fourth 270′ parts. The first 260 andsecond 270 parts include complementary mating features 261, 271 to allowfor disconnection and sealing reconnection. The first 260 and second 270parts together form the first chamber 298 of the container 200. A firstmaterial may be disposed in the first part 260 and the second part 270may be connected to the first part 260 to seal the material in the firstchamber 298. A rupturable membrane 250 prevents the material fromexiting the sealed first chamber 298. The third part 260′ includes acomplementary mating feature 261′ to a mating feature 271′ of the secondpart 270 to allow for disconnection and sealing reconnection. The second270, third 260′, and fourth 270′ parts together form the second chamber299. The third part 260′ includes a complementary mating feature 261″ toa mating feature 271″ of the fourth part 270′ to allow for disconnectionand sealing reconnection. When the second 270 and third 260′ parts areconnected, a second material may be introduced in the third part 260′.The fourth part 270′ may then be sealingly connected to the third part260′. The fourth part 270′ includes a rupturable membrane 250′ toprevent the contents of the second chamber 299 from leaking or spilling.The rupturable membrane 250 prevents interaction between the contents ofthe first 298 and second 299 chambers during storage. Upon rupture ofthe membrane 250 in use, the contents of the first 298 and secondchambers 299 can mix.

In the embodiment depicted in FIG. 22, the container 200 includes first260, second 260′, and third 270′ parts. The first 260 and second 260′parts include complementary mating features 261, 271 to allow fordisconnection and sealing reconnection. The first 260 and second 270parts together form the first chamber 298 of the container 200. A firstmaterial may be disposed in the first part 260 and the second part 270may be connected to the first part 260 to seal the material in the firstchamber 298. A rupturable membrane 250 prevents the material fromexiting the sealed first chamber 298. The third part 270′ includes acomplementary mating feature 271′ to a mating feature 261′ of the secondpart 260′ to allow for disconnection and sealing reconnection. Thesecond 260′ and third 270′ parts together form the second chamber 299. Asecond material may be introduced in the second part 260′. The thirdpart 270′ may then be sealingly connected to the second part 260′. Thethird part 270′ includes a rupturable membrane 250′ to prevent thecontents of the second chamber 299 from leaking or spilling. Therupturable membrane 250 prevents interaction between the contents of thefirst 298 and second 299 chambers during storage. Upon rupture of themembrane 250 in use, the contents of the first 298 and second chambers299 can mix.

In the embodiments depicted in FIGS. 21-22, the moveable sealing memberincludes a tapered distal region that may serve as a piercing element tofacilitate rupturing membranes 250, 250′.

While not described at length herein, it will be understood that thebiologic agent to be delivered may be delivered in any form, e.g. liquidor solid. By using a system as described herein, solid forms and liquidforms of the biologic agent should be readily interchangeable withoutthe need to design and develop new catheters or components of thesystem. Examples of suitable solid forms of biologics that may bedelivered in accordance with the teachings provided herein includelyophilized particles or solid scaffolds. In many circumstances, solidscaffolds are considered more effective for delivering therapy to ahighly vascularized region such as the myocardium.

The various embodiments shown and described herein include variouscomponents. One of skill in the art will readily understand thatcomponents of a given described embodiment may be readily substitutedfor, or used in addition to, components of a different describedembodiment.

Thus, embodiments of the SYSTEM AND METHOD FOR DELIVERY OF BIOLOGICAGENTS are disclosed. One skilled in the art will appreciate that thepresent invention can be practiced with embodiments other than thosedisclosed. The disclosed embodiments are presented for purposes ofillustration and not limitation, and the present invention is limitedonly by the claims that follow.

What is claimed is:
 1. A system for delivering a therapeutic agent to apatient, comprising: a catheter having a proximal end and a distal endand comprising a body defining a lumen extending to the distal end ofthe catheter; filter disposed across the entire width of the catheterlumen in proximity to the distal end of the catheter body, the filterbeing configured to allow the therapeutic agent to exit the lumen and toprevent unintended particulate matter from exiting the lumen; acontainer insertable and slidably disposable in the lumen of thecatheter, the container having a first chamber for housing thetherapeutic agent, a second chamber and a rupturable membrane betweenthe first chamber and the second chamber to prevent mixing of thetherapeutic agent and the contents of the second chamber during storageof the container, wherein the rupturable membrane comprises aself-sealing septum, wherein the container comprises a sealing memberdistally moveable in the container; a stop feature in proximity to thedistal end of the catheter, wherein the container is configured toengage the stop feature and to inhibit the container from exiting thelumen, a first bar slidably disposable in the lumen, wherein sliding thefirst bar distally in the lumen causes the membrane between the firstand second chamber of the container to rupture and forces thetherapeutic agent out of the container and out of the lumen when thecontainer is engaged with the stop feature, wherein the catheter is aflexible catheter configured to follow a non-linear path through thepatient.
 2. The system of claim 1, further comprising a second barhaving a body member defining a lumen configured to receive the firstbar, wherein the first bar is axially slidable within the lumen, andwherein distally sliding the second bar in the lumen causes thecontainer to move distally in the catheter lumen.
 3. The system of claim1, wherein distal sliding of the first bar in the catheter lumen isconfigured to cause the sealing member to move distally when thecontainer engages the stop feature and to cause the membrane between thefirst and second chamber to rupture.
 4. The system of claim 3, whereinthe moveable sealing member comprises a tapered distal region thatserves as a piercing element to facilitate rupturing the membranebetween the first and second chambers of the container.
 5. The system ofclaim 4, wherein the container comprises a second rupturable membraneconfigured to prevent the leakage or spillage of the contents of thesecond chamber from the container, and wherein the tapered distal regionof the sealing member is configured to facilitate rupturing of thesecond membrane.
 6. A system for delivering a therapeutic agent to apatient, comprising: a catheter having a proximal end and a distal endand comprising a body defining a lumen extending to the distal end ofthe catheter; a container insertable and slidably disposable in thelumen of the catheter, the container having a first chamber for housingthe therapeutic agent, a second chamber and a rupturable membranebetween the first chamber and the second chamber to prevent mixing ofthe therapeutic agent and the contents of the second chamber duringstorage of the container; a stop feature in proximity to the distal endof the catheter, wherein the container is configured to engage the stopfeature and to inhibit the container from exiting the lumen, a first barslidably disposable in the lumen, wherein sliding the first bar distallyin the lumen causes the membrane between the first and second chamber ofthe container to rupture and forces the therapeutic agent out of thecontainer and out of the lumen when the container is engaged with thestop feature, wherein the container comprises first, second and thirdparts, wherein the first part and the second part include complementarymating features to allow for disconnection and resealing reconnection ofthe first and second parts, wherein the first and second parts togetherform the first chamber, wherein the second part includes the rupturablemembrane that separates the first and second chambers, wherein thesecond part and the third part include complementary mating features toallow for disconnection and resealing reconnection of the second andthird parts, and wherein the second and third parts together form thesecond chamber.
 7. A system for delivering a therapeutic agent to apatient, comprising: a catheter having a proximal end and a distal endand comprising a body defining a lumen extending to the distal end ofthe catheter; a container insertable and slidably disposable in thelumen of the catheter, the container having a first chamber for housingthe therapeutic agent, a second chamber and a rupturable membranebetween the first chamber and the second chamber to prevent mixing ofthe therapeutic agent and the contents of the second chamber duringstorage of the container; a stop feature in proximity to the distal endof the catheter, wherein the container is configured to engage the stopfeature and to inhibit the container from exiting the lumen, a first barslidably disposable in the lumen, wherein sliding the first bar distallyin the lumen causes the membrane between the first and second chamber ofthe container to rupture and forces the therapeutic agent out of thecontainer and out of the lumen when the container is engaged with thestop feature, wherein the container comprises first, second, third andfourth parts, wherein the first part and the second part includecomplementary mating features to allow for disconnection and resealingreconnection of the first and second parts, wherein the first and secondparts together form the first chamber, wherein the second part includesthe rupturable membrane that separates the first and second chambers,wherein the second part and the third part include complementary matingfeatures to allow for disconnection and resealing reconnection of thesecond and third parts, wherein the third part and the fourth partinclude complementary mating features to allow for disconnection andresealing reconnection of the third and fourth parts, and wherein thesecond, third, and fourth parts together form the second chamber.
 8. Asystem for delivering a therapeutic agent to a patient, comprising: acatheter having a proximal end and a distal end and comprising a bodydefining a lumen extending to the distal end of the catheter; acontainer insertable and slidably disposable in the lumen of thecatheter, the container having a first chamber for housing thetherapeutic agent, a second chamber and a rupturable membrane betweenthe first chamber and the second chamber to prevent mixing of thetherapeutic agent and the contents of the second chamber during storageof the container; a stop feature in proximity to the distal end of thecatheter, wherein the container is configured to engage the stop featureand to inhibit the container from exiting the lumen; a first barslidably disposable in the lumen, wherein sliding the first bar distallyin the lumen causes the membrane between the first and second chamber ofthe container to rupture and forces the therapeutic agent out of thecontainer and out of the lumen when the container is engaged with thestop feature; and filter disposed across the entire width of thecatheter lumen in proximity to the distal end of the catheter body, thefilter being configured to allow the therapeutic agent to exit the lumenand to prevent unintended particulate matter from exiting the lumen. 9.A container configured to be insertable and slidably disposable in alumen of a catheter such that pushing the container within the catheterlumen against a stop feature in proximity to the distal end of thecatheter causes contents of the container to exit the lumen of thecatheter, the container comprising: a first chamber for housing thetherapeutic agent, a second chamber and a rupturable membrane betweenthe first chamber and the second chamber to prevent mixing of contentsof the first and second chambers during storage of the container;wherein the rupturable membrane is configured to rupture, allowingcontents of the first and second chambers to mix when the container ispushed against the stop feature of the catheter, wherein the containercomprises first, second, third and fourth parts, wherein the first andsecond parts include complementary mating features to allow fordisconnection and sealing reconnection of the first and second parts,wherein the first and second parts, when connected, form the firstchamber, wherein the second and third parts include complementary matingfeatures to allow for disconnection and sealing reconnection of thesecond and third parts, wherein the third and fourth parts includecomplementary mating features to allow for disconnection and sealingreconnection of the third and fourth parts, and wherein the second,third and fourth parts, when connected, form the second chamber.
 10. Thecontainer of claim 9, wherein the second part comprises the rupturablemembrane.
 11. The container of claim 9, further comprising a sealingmember sealingly moveable through at a portion of the first and secondchambers along at least a portion of the first, second, third and fourthparts.
 12. A container configured to be insertable and slidablydisposable in a lumen of a catheter such that pushing the containerwithin the catheter lumen against a stop feature in proximity to thedistal end of the catheter causes contents of the container to exit thelumen of the catheter, the container comprising: a first chamber forhousing the therapeutic agent, a second chamber and a rupturablemembrane between the first chamber and the second chamber to preventmixing of contents of the first and second chambers during storage ofthe container; wherein the rupturable membrane is configured to rupture,allowing contents of the first and second chambers to mix when thecontainer is pushed against the stop feature of the catheter, whereinthe container comprises first, second and third parts, wherein the firstand second parts include complementary mating features to allow fordisconnection and sealing reconnection of the first and second parts,wherein the first and second parts, when connected, form the firstchamber, wherein the second and third parts include complementary matingfeatures to allow for disconnection and sealing reconnection of thesecond and third parts, and wherein the second and third, whenconnected, form the second chamber.
 13. The container of claim 12,wherein the second part comprises the rupturable membrane.
 14. Thecontainer of claim 12, further comprising a sealing member sealinglymoveable through at a portion of the first and second chambers along atleast a portion of the first, second, third and fourth parts.
 15. Asystem for delivering a therapeutic agent to a patient, comprising: acatheter having a proximal end and a distal end and comprising a bodydefining a lumen extending to the distal end of the catheter, whereinthe catheter is a flexible catheter configured to follow a non-linearpath through the patient; a container insertable and slidably disposablein the lumen of the catheter, the container having a first chamber forhousing the therapeutic agent, a second chamber and a rupturablemembrane between the first chamber and the second chamber to preventmixing of the therapeutic agent and the contents of the second chamberduring storage of the container, wherein the rupturable membranecomprises a self-sealing septum; a stop feature in proximity to thedistal end of the catheter, wherein the container is configured toengage the stop feature and to inhibit the container from exiting thelumen; a first bar slidably disposable in the lumen, wherein sliding thefirst bar distally in the lumen causes the membrane between the firstand second chamber of the container to rupture and forces thetherapeutic agent out of the container and out of the lumen when thecontainer is engaged with the stop feature; and a filter disposed acrossthe entire width of the catheter lumen in proximity to the distal end ofthe catheter body, the filter being configured to allow the therapeuticagent to exit the lumen and to prevent unintended particulate matterfrom exiting the lumen.